Amyloid precursor protein (APP) proteolysis is the fundamental process for the production of ?-amyloid (A?) peptides implicated in Alzheimer's disease (AD) pathology. Since 1-secretase cleaves within the A? peptide domain, its activation may have the double advantage of not only precluding the neurotoxic A? peptide formation, but also generating the putatively neuroprotective sAPP-?. Thus, it would appear highly advantageous to shift APP cleavage from the amyloidogenic 2-secretase to the non-amyloidogenic ?- secretase cleavage. Our recent data show that green tea derived (-)-epigallocatechin-3-gallate (EGCG) reduces A? peptide generation in "Swedish" mutant APP-overexpressing primary neurons (Tg2576 mouse- derived primary neuronal cells) and neuron-like cells (SweAPP N2a cells). In concert with these observations, we found that EGCG markedly activates cleavage of 1-CTF and elevates sAPP-1 (Rezai-Zadeh et al., 2005). These cleavage events are associated with elevated 1-secretase cleavage activity and enhanced activation of a disintegrin and metalloprotease 10 (ADAM10), a primary candidate for 1-secretase (Obregon et al., 2006). As a validation of these findings in vivo, we treated A?-overproducing Tg2576 transgenic mice intraperitoneally with EGCG and found significantly decreased A? levels/plaques in the brain (Rezai-Zadeh et al., 2005). These effects are associated with promotion of the non-amyloidogenic 1-secretase proteolytic pathway. In this proposal, we will evaluate EGCG's therapeutic effect on reducing cerebral amyloidosis and improving cognitive impairment in a transgenic mouse model of AD via an oral administration. In Aim 1, we will employ oral administration of green tea-EGCG (TeaMemTM) to Tg2576 mice before (prophylactic treatment group) and after (therapeutic treatment group) the development of AD-like pathology. Groups of untreated non-transgenic littermates compared to the transgenic treatment groups. Oral administration of TeaMemTM or vehicle (H2O) to Tg2576 mice will be performed for 6 months. Following the administration, we will sacrifice these mice at several ages to examine histologic and biochemical endpoints. Furthermore, following more long-term TeaMemTM administration, cognitive testing will be done prior to euthanasia. In Aim 2, we will employ oral administration of TeaMemTM in the presence or absence of piperine to Tg2576 mice before (prophylactic treatment group) and after (therapeutic treatment group) the development of AD-like pathology for 6 months. In this study, we plan to evaluate two time points comparing TeaMemTM alone to TeaMemTM plus piperine. Groups will be compared by their effects on reducing AD-like pathology and opposing behavioral impairment. These studies could lay the foundation for AD clinical trials with pure TeaMemTM or/and piperine in the near future. PUBLIC HEALTH RELEVANCE: In this proposal, we will fully characterize the effect of green tea derived EGCG (TeaMemTM) on increasing non-amyloidogenic 1-secretase cleavage and evaluate its therapeutic effect on reducing cerebral amyloidosis and being beneficial to cognitive impairment in a transgenic mouse model of Alzheimer's disease (AD). These studies will lay the foundation for AD clinical trials with pure TeaMemTM or/and piperine (an alkaloid derived from black pepper) in the near future.